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Background Crohn’s disease (CD) is highly heterogenous and may be complicated by stricturing behavior. Personalized prediction of stricturing will inform management. We aimed to create a stricturing risk stratification model using genomic/clinical data. Methods Exome sequencing was performed on CD patients, and phenotype data retrieved. Biallelic variants in NOD2 were identified. NOD2 was converted into a per-patient deleteriousness metric (“GenePy”). Using training data, patients were stratified into risk groups for fibrotic stricturing using NOD2. Findings were validated in a testing data set. Models were modified to include disease location at diagnosis. Cox proportional hazards assessed performance. Results Six hundred forty-five patients were included (373 children and 272 adults); 48 patients fulfilled criteria for monogenic NOD2-related disease (7.4%), 24 of whom had strictures. NOD2 GenePy scores stratified patients in training data into 2 risk groups. Within testing data, 30 of 161 patients (18.6%) were classified as high-risk based on the NOD2 biomarker, with stricturing in 17 of 30 (56.7%). In the low-risk group, 28 of 131 (21.4%) had stricturing behavior. Cox proportional hazards using the NOD2 risk groups demonstrated a hazard ratio (HR) of 2.092 (P = 2.4 × 10-5), between risk groups. Limiting analysis to patients diagnosed aged Conclusions A NOD2 genomic biomarker predicts stricturing risk, with prognostic power improved in pediatric-onset CD. Implementation into a clinical setting can help personalize management.

Studies of Crohn’s disease have consistently implicated NOD2 as the most important gene in disease pathogenesis since first being identified in 2001. Thereafter, genome-wide association, next-generation sequencing and functional analyses have all confirmed a key role for NOD2, but despite this, NOD2 also has significant unresolved complexity. More recent studies have reinvigorated an early hypothesis that NOD2 may be a single-gene cause of disease, and the distinct ileal stricturing phenotype seen with NOD2-related disease presents an opportunity for personalized diagnosis, disease prediction and targeted therapy. The genomics of NOD2 has much that remains unknown, including the role of rare variation, phasing of variants across the haplotype block and the role of variation in the NOD2-regulatory regions. Here, we discuss the evidence and the unmet needs of NOD2 research, based on recently published evidence, and suggest methods that may meet these requirements.

To determine how the use of biological therapy is associated with surgical intervention for paediatric inflammatory bowel disease (PIBD) at a population level.Hospital Episode Statistics data were obtained for all admissions within England (1997-2015), in children aged 0-18 years, with an ICD-10 code for diagnosis of Crohn disease (CD), ulcerative colitis (UC), or inflammatory bowel disease-unclassified (IBD-U). Office of Population Censuses and Surveys Classification of Surgical Operations and Procedures codes for major surgical resection associated with PIBD and for biological therapy were also obtained. Data are presented as median values (interquartile range).In total, 22,645 children had a diagnosis of PIBD of which 13,722 (61%) had CD, 7604 (34%) had UC, and 1319 (5.8%) cases had IBD-U. Biological therapy was used in 4054 (17.9%) cases. Surgical resection was undertaken in 3212 (14%) cases, more commonly for CD than UC (17.5 vs 10.3%, P0.0001). Time from diagnosis to major surgical resection was 8.3 (1.2-28.2) months in CD and 8.2 (0.8-21.3) months in UC. As the time-frame of the dataset progressed, there was a decreased rate of surgical intervention ( P = 0.04) and an increased use of biological therapy ( P0.0001). Additionally, the number of new diagnoses of PIBD increased.The introduction of biologic agents has been associated with a reduction in cases undergoing surgery in children with a known diagnosis of PIBD. As time progresses we will be able to determine whether biological therapies prevent the need for surgery altogether or just delay this until adulthood.

Abstract The rise of machine learning in healthcare has significant implications for paediatrics. Long-term conditions with significant disease heterogeneity comprise large portions of the routine work performed by paediatricians. Improving outcomes through discovery of disease and treatment prediction models, alongside novel subgroup clustering of patients, are some of the areas in which machine learning holds significant promise. While artificial intelligence has percolated into routine use in our day to day lives through advertising algorithms, song or movie selections and sifting of spam emails, the ability of machine learning to utilise highly complex and dimensional data has not yet reached its full potential in healthcare. In this review article, we discuss some of the foundations of machine learning, including some of the basic algorithms. We emphasise the importance of correct utilisation of machine learning, including adequate data preparation and external validation. Using nutrition in preterm infants and paediatric inflammatory bowel disease as examples, we discuss the evidence and potential utility of machine learning in paediatrics. Finally, we review some of the future applications, alongside challenges and ethical considerations related to application of artificial intelligence. Impact Machine learning is a widely used term; however, understanding of the process and application to healthcare is lacking. This article uses clinical examples to explore complex machine learning terms and algorithms. We discuss limitations and potential future applications within paediatrics and neonatal medicine.

Objective: The incidence of paediatric inflammatory bowel disease (IBD) has been increasing over 25 years; however, contemporary trends are not established and the impact of COVID-19 on case rates is unclear. Methods: Data from Southampton Children's hospital prospective IBD database were retrieved for 2002-2021. Incidence rates were calculated based on referral area populations and temporal trends analysed. Disease prevalence for those aged -6, driven by Crohn's disease, β = 0.732, P = 0.00024 and ulcerative colitis, β = 0.816, P = 0.000011. There was no change in IBDU incidence, β = 0.230, P = 0.33. From 2002-2021, 51 patients were diagnosed -7). There was no significant change in incidence of IBD in

Background Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with two main subtypes: Crohn’s disease (CD) and Ulcerative Colitis (UC). Prompt subtype diagnosis enables the correct treatment to be administered. Using genomic data, we aimed to assess machine learning (ML) to classify patients according to IBD subtype. Methods Whole exome sequencing from paediatric/adult IBD patients was processed using an in-house bioinformatics pipeline. This data was condensed into the per-gene, per-individual genomic burden score, GenePy. Data was split into training and testing datasets (80/20). Feature selection with a linear support vector classifier, and hyperparameter tuning with Bayesian Optimisation was performed (training data). The supervised ML method random forest was utilised to classify patients as CD or UC using three panels: I) all available genes, 2) autoimmune genes, 3) ‘IBD’ genes. ML results were assessed using AUROC, sensitivity and specificity on the testing dataset. Results 906 patients were included in analysis (600 CD, 306 UC). Training data included 488 patients, balanced according to the minority class of UC. The autoimmune gene panel generated the best performing ML model (AUROC=0.68), outperforming an IBD gene panel (AUROC =0.61). NOD2 was the top gene for discriminating CD and UC, regardless of the gene panel used. Lack of variation in genes with high GenePy scores in CD patients was the best classifier of a diagnosis of UC. Discussion We demonstrate promising classification of patients by subtype utilising random forest and WES data. Focussing on specific subgroups of patients, with larger datasets may result in better classification.

Background/Objective– Heterogeneity and chronicity of Crohn’s disease (CD) make prediction of outcomes difficult. To date, no longitudinal measure can quantify burden over a patient’s disease course, preventing assessment and integration into predictive modelling. Here, we aimed to demonstrate the feasibility of constructing a data driven, longitudinal disease burden score.Methods– Literature was reviewed for tools used in assessment of CD activity. Themes were identified to construct a paediatric CD morbidity index (PCD-MI). Scores were assigned to variables. Data were extracted automatically from the electronic patient records at Southampton Children’s Hospital, diagnosed from 2012 to 2019 (inclusive). PCD-MI scores were calculated, adjusted for duration of follow up and assessed for variation (ANOVA) and distribution (Kolmogorov-Smirnov).Results– Nineteen clinical/biological features across five themes were included in the PCD-MI including blood/faecal/radiological/endoscopic results, medication usage, surgery, growth parameters and extraintestinal manifestations. Maximal score was 100 after accounting for follow-up duration.PCD-MI was assessed in 66 patients, mean age 12.5 years. Following quality filtering, 9528 blood/faecal test results and 1309 growth measures were included. Mean PCD-MI score was 14.95 (range 2.2-32.5), data were normally distributed (p=0.2) with 25% of patients having a PCD-MI Conclusions– PCD-MI is a calculatable measure for a cohort of patients diagnosed over an 8-year period, integrating a wide-range of data with potential to determine high or low disease burden. Future iterations of the PCD-MI require refinement of included features, optimised scores and validation on external cohorts.

Background: Growth failure in infants born with CHD is a persistent problem, even in those provided with adequate nutrition. Objective: To summarise the published data describing the change in urinary metabolites during metabolic maturation in infants with CHD and identify pathways amenable to therapeutic intervention Design: Scoping review. Eligibility criteria: Studies using qualitative or quantitative methods to describe urinary metabolites pre- and post-cardiac surgery and the relationship with growth in infants with CHD. Sources of evidence: NICE Healthcare Databases website was used as a tool for multiple searches. Results: 347 records were identified, of which 37 were duplicates. Following the removal of duplicate records, 310 record abstracts and titles were screened for inclusion. The full texts of eight articles were reviewed for eligibility, of which only two related to infants with CHD. The studies included in the scoping review described urinary metabolites in 42 infants. A content analysis identified two overarching themes of metabolic variation predictive of neurodevelopmental abnormalities associated with anaerobic metabolism and metabolic signature associated with the impact on gut microbiota, inflammation, energy, and lipid digestion. Conclusion: The results of this scoping review suggest that there are considerable gaps in our knowledge relating to metabolic maturation of infants with CHD, especially with respect to growth. Surgery is a key early life feature for CHD infants and has an impact on the developing biochemical phenotype with implications for metabolic pathways involved in immunomodulation, energy, gut microbial, and lipid metabolism. These early life fingerprints may predict those individuals at risk for neurodevelopmental abnormalities.

Background: Paediatric Crohn's disease (CD) has been associated with undernutrition. Accurate and accessible measures of body composition would provide data to personalise nutritional therapy. We assessed feasibility of MRI-derived measures of psoas cross-sectional area (PCSA) in paediatric CD and correlated with anthropometric and bioelectrical impedance spectroscopy (BIS) measures. Methods: MRI small bowel/pelvis images of patients with CD, aged

Background: the COVID-19 pandemic has had wide-reaching primary and secondary health implications. The UK government implemented a national lockdown to slow the rate of infection at the end of March 2020, lasting until early summer 2020. The results from a UK nationwide survey suggest the majority of inflammatory bowel disease patients were followed up using technology-enabled care services (TECS) during this time. We therefore aimed to explore the impact of the pandemic on nutritional status of children with inflammatory bowel disease, focusing on the effect of national lockdown from March to early summer 2020. Methods: a retrospective study was conducted. All patients with a diagnosis of inflammatory bowel disease, aged Results: in total, 116 patients had paired measures. Using the World Health Organization criteria of nutritional status, 19% (n = 22/116) were mildly malnourished with a body mass index Z score (BMIZ) −1 to 1) (n = 0/43) children (p ≤ 0.0001) had a TECS nutrition review. Conclusions: dietetic reviews were severely restricted during the first national lockdown. Patients with low BMIZ prior to lockdown became more malnourished. During the ongoing pandemic, it is important to identify those children with nutrition risk, focusing support on this group of children.

Background and Aims Crohn’s disease [CD] arises through host-environment interaction. Abnormal gene expression results from disturbed pathway activation or response to bacteria. We aimed to determine activated pathways and driving cell types in paediatric CD. Methods We employed contemporary targeted autoimmune RNA sequencing, in parallel to single-cell sequencing, to ileal tissue derived from paediatric CD and controls. Weighted gene co-expression network analysis [WGCNA] was performed and differentially expressed genes [DEGs] were determined. We integrated clinical data to determine co-expression modules associated with outcomes. Results In all, 27 treatment-naive CD [TN-CD], 26 established CD patients and 17 controls were included. WGCNA revealed a 31-gene signature characterising TN-CD patients, but not established CD, nor controls. The CSF3R gene is a hub within this module and is key in neutrophil expansion and differentiation. Antimicrobial genes, including S100A12 and the calprotectin subunit S100A9, were significantly upregulated in TN CD compared with controls [p = 2.61 x 10-15 and p = 9.13 x 10-14, respectively] and established CD [both p = 0.0055]. Gene-enrichment analysis confirmed upregulation of the IL17-, NOD- and Oncostatin-M-signalling pathways in TN-CD patients, identified in both WGCNA and DEG analyses. An upregulated gene signature was enriched for transcripts promoting Th17-cell differentiation and correlated with prolonged time to relapse [correlation-coefficient-0.36, p = 0.07]. Single-cell sequencing of TN-CD patients identified specialised epithelial cells driving differential expression of S100A9. Cell groups, determined by single-cell gene expression, demonstrated enrichment of IL17-signalling in monocytes and epithelial cells. Conclusions Ileal tissue from treatment-naïve paediatric patients is significantly upregulated for genes driving IL17-, NOD- and Oncostatin-M-signalling. This signal is driven by a distinct subset of epithelial cells expressing antimicrobial gene transcripts.

ObjectiveChronic diseases, such as inflammatory bowel disease (IBD), can impact negatively on education and social development. Examining the impact of IBD on school/college attendance for children and young people (CYP) is vital to provide targeted support to patients, families and schools.MethodsWe performed a cross-sectional survey to determine the school/college attendance rates, the reasons for absence related to IBD and facilitators or barriers to school/college attendance. In a subset of patients followed up locally, we performed a detailed review of hospital attendance data to assess healthcare burden.ResultsTwo hundred and thirty-one questionnaires were given to CYP with IBD aged 5–17 years. Response rate was 74% (final sample 169). The median school/college attendance rate was 92.5%, significantly lower than all children in England (95.2%). 39.6% of children with IBD were persistently absent, defined nationally as missing 10% or more of school. Only five children (3%) had a 100% attendance record. Increasing age and use of monoclonal therapy were predictors of poor school attendance. Concerns about feeling unwell at school/college, access to toilets, keeping up with work and teachers’ understanding of IBD are the main issues for CYP with IBD. There was a significant negative correlation between number of days in hospital and school attendance.ConclusionIBD has a significant impact on school/college attendance, with hospital attendance, disease burden and school difficulties being major factors. Employing strategies to minimise healthcare burden and developing a partnership between health and education to support children with IBD will serve to facilitate school/college attendance.

Background: Growth failure in infants born preterm is a significant issue, increasing the risk of poorer neurodevelopmental outcomes and metabolic syndrome later in life. During the first 1000 days of life biological systems mature rapidly involving developmental programming, cellular senescence, and metabolic maturation, regulating normal growth and development. However, little is known about metabolic maturation in infants born preterm and the relationship with growth. Objective: To examine the available evidence on urinary markers of metabolic maturation and their relationship with growth in infants born preterm. Eligibility criteria: Studies including in this scoping review using qualitative or quantitative methods to describe urinary markers of metabolic maturation and the relationship with growth in infants born preterm. Results: After a screening process 15 titles were included in this review, from 1998–2021 drawing from China (n = 1), Italy (n = 3), Germany (n = 3), Greece (n = 1), Japan (n = 2), Norway (n = 1), Portugal (n = 1), Spain (n = 2) and USA (n = 1). The included studies examined urinary metabolites in 1131 infants. A content analysis identified 4 overarching themes relating to; (i) metabolic maturation relative to gestational age, (ii) metabolic signature and changes in urinary metabolites over time, (iii) nutrition and (iv) growth. Conclusion: The results of this scoping review suggest there are considerable gaps in our knowledge relating to factors associated with metabolic instability, what constitutes normal maturation of preterm infants, and how the development of reference phenome age z scores for metabolites of interest could improve nutritional and growth outcomes.

Background & aims: Nutritional assessment in paediatric inflammatory bowel disease (IBD) is key to supporting growth whilst minimising adiposity. Bedside assessment using bioelectrical impedance spectroscopy (BIS) has previous identified patients with declining cellular and nutritional health. We aimed to assess BIS measures in stable paediatric IBD patient. Methods: Stable IBD patients were recruited at routine hospital visits. All patients underwent BIS, anthropometry and disease activity assessment. Multivariable regression and receiver operator curve (ROC) analyses were undertaken to assess the utility of BIS phase angle 50 KHz (PA-50) and 200/5 KHz impedance ratio (IR) in nutritional assessment. Results: There were 140 study visits from 97 patients, mean age 14.49 years, 62.9% Crohn's disease. Mean BMI Z-score (BMIZ) was 0.31 (range −2.97 to 3.99), 33% of patients were overweight (BMIZ>1) and 13.8% of patients were underweight (BMIZ < −1). Crohn's disease patients had a lower mean BMIZ score 0.14, compared to ulcerative colitis, 0.68, p = 0.007. There was no relationship between PA-50 and BMIZ or disease activity. IR was not related to disease activity but was negatively related to BMIZ in a multivariable regression, accounting for age, sex and disease subtype (beta −0.331, p = 0.001). ROC analyses did not identify a clinically useful cut off for either PA-50 or IR to identify patients with active disease, biologic use or BMIZ>1 or < -1. Conclusion: BIS appears to have limited added value in nutritional assessment of stable paediatric IBD patients. Nearly 1/3 patients were overweight and personalised approach to supplementation is vital to avoid overnutrition.

OBJECTIVES: Patients with paediatric inflammatory bowel disease (IBD) constitute one of the largest cohorts requiring transition from paediatric to adult services. Standardised transition care improves short and long-term patient outcomes. This study aimed to detail the current state of transition services for IBD in the United Kingdom (UK). METHODS: We performed a nationwide study to ascertain current practice, facilities and resources for children and young people with IBD. Specialist paediatric IBD centres were invited to contribute data on: timing of transition/transfer of care; transition resources available including clinics, staff and patient information; planning for future improvement. RESULTS: Twenty of 21 (95%) of invited centres responded. Over 90% of centres began the transition process below 16 years of age and all had completed transfer to adult care at 18 years of age. The proportion of patients in the transition process at individual centres varied from 10% to 50%.Joint clinics were held in every centre, with a mean of 12.9 clinics per year. Adult and paediatric gastroenterologists attended at all sites. Availability of additional team members was patchy across the UK, with dietetic, psychological and surgical attendance available in

The assessment and management of patients with known, or suspected, paediatric inflammatory bowel disease (PIBD) has been hugely impacted by the COVID-19 pandemic. Although current evidence of the impact of COVID-19 infection in children with PIBD has provided a degree of reassurance, there continues to be the potential for significant secondary harm caused by the changes to normal working practices and reorganisation of services.Disruption to the normal running of diagnostic and assessment procedures, such as endoscopy, has resulted in the potential for secondary harm to patients including delayed diagnosis and delay in treatment. Difficult management decisions have been made in order to minimise COVID-19 risk for this patient group while avoiding harm. Initiating and continuing immunosuppressive and biological therapies in the absence of normal surveillance and diagnostic procedures have posed many challenges.Despite this, changes to working practices, including virtual clinic appointments, home faecal calprotectin testing kits and continued intensive support from clinical nurse specialists and other members of the multidisciplinary team, have resulted in patients still receiving a high standard of care, with those who require face-to-face intervention being highlighted.These changes have the potential to revolutionise the way in which patients receive routine care in the future, with the inclusion of telemedicine increasingly attractive for stable patients. There is also the need to use lessons learnt from this pandemic to plan for a possible second wave, or future pandemics as well as implementing some permanent changes to normal working practices.In this review, we describe the diagnosis, management and direct impact of COVID-19 in paediatric patients with IBD. We summarise the guidance and describe the implemented changes, evolving evidence and the implications of this virus on paediatric patients with IBD and working practices.

BackgroundCOVID-19 has impacted on healthcare provision. Anecdotally, investigations for children with inflammatory bowel disease (IBD) have been restricted, resulting in diagnosis with no histological confirmation and potential secondary morbidity. In this study, we detail practice across the UK to assess impact on services and document the impact of the pandemic.MethodsFor the month of April 2020, 20 tertiary paediatric IBD centres were invited to contribute data detailing: (1) diagnosis/management of suspected new patients with IBD; (2) facilities available; (3) ongoing management of IBD; and (4) direct impact of COVID-19 on patients with IBD.ResultsAll centres contributed. Two centres retained routine endoscopy, with three unable to perform even urgent IBD endoscopy. 122 patients were diagnosed with IBD, and 53.3% (n=65) were presumed diagnoses and had not undergone endoscopy with histological confirmation. The most common induction was exclusive enteral nutrition (44.6%). No patients with a presumed rather than confirmed diagnosis were started on anti-tumour necrosis factor (TNF) therapy.Most IBD follow-up appointments were able to occur using phone/webcam or face to face. No biologics/immunomodulators were stopped. All centres were able to continue IBD surgery if required, with 14 procedures occurring across seven centres.ConclusionsDiagnostic IBD practice has been hugely impacted by COVID-19, with >50% of new diagnoses not having endoscopy. To date, therapy and review of known paediatric patients with IBD has continued. Planning and resourcing for recovery is crucial to minimise continued secondary morbidity.

Activation of the nuclear factor (NF)-κB transcription factor is instrumental for the immune response and the survival of peripheral activated T cells. We demonstrate that ligation of CD95 (Fas/APO1), a potent apoptotic stimulus in lymphocytes, results in repression of NF-κB activity in Jurkat T cells by inducing the proteolytic cleavage of NF-κB p65 (Rel A) and p50. Inhibition of caspase-3-related proteases by a specific acetylated aldehyde (Ac-DEVD-CHO) prevented CD95-induced cleavage of p65 (RelA) or p50 and restored the inducibility of NF-κB in cells treated with an antibody against CD95. The addition of recombinant caspase-3 also resulted in proteolytic cleavage of RelA p65 and p50 in vitro. TNF-α treatment, unlike CD95 ligation, did not result in the death of Jurkat cells but did so in the presence of IκBαM, a transdominant inhibitor of NF-κB. These results suggest that intact, functional NF-κB maintains the survival of activated T cells, and that CD95-induced cleavage of NF-κB subunits sensitizes T cells to apoptosis and, hence, facilitates the decay of an immune response.

What you need to know A 29 year old white woman presents to her general practitioner with a 12 month history of borderline anaemia (diagnosed when she tried to donate blood) alongside increasing bloating at the end of every day. On direct questioning, she has slightly looser stools compared with 5-10 years ago, but this has been attributed to irritable bowel syndrome by both the patient and previous GPs. She has no other medical history, including normal menarche. The GP decides to order some blood tests including a tissue transglutaminase (TTG) IgA test, which gives a result of 78.4 U/mL (normal range 0.0-4.5 U/mL), with normal total IgA (normal range 0.80-2.8 g/L). Coeliac disease is a common autoimmune condition, often presenting with vague symptoms triggered by chronic gluten ingestion in genetically predisposed individuals. It is characterised by the presence of specific autoantibodies with a coexisting enteropathy.1 It is more common in females (1.5:1 predominance) and in populations with European ancestry, with an estimated prevalence of 1.4% globally.123 Despite growing recognition of coeliac disease, many cases remain undiagnosed: a North American study spanning 2006 to 2011 of over 30 000 individuals without a known coeliac disease diagnosis demonstrated coeliac-positive serology in 1.1%.4 The classic symptoms usually trigger testing, but patients with less common presentations are often not screened for coeliac disease.1 Timely diagnosis is important, …

Objectives: The current classification of inflammatory bowel disease (IBD) is based on clinical phenotypes, which is blind to the molecular basis of the disease. The aim of this study was to stratify a treatment-naïve paediatric IBD cohort through specific innate immunity pathway profiling and application of unsupervised machine learning (UML).Methods: In order to test the molecular integrity of biological pathways implicated in IBD, innate immune responses were assessed at diagnosis in 22 paediatric patients and 10 age-matched controls. Peripheral blood mononuclear cells (PBMCs) were selectively stimulated for assessing the functionality of upstream activation receptors including NOD2, toll-like receptor (TLR) 1-2 and TLR4, and the downstream cytokine responses (IL-10, IL-1β, IL-6, and TNF-α) using multiplex assays. Cytokine data generated were subjected to hierarchical clustering to assess for patient stratification.Results: Combined immune responses in patients across 12 effector responses were significantly reduced compared with controls (P = 0.003) and driven primarily by “hypofunctional” TLR responses (P values 0.045, 0.010, and 0.018 for TLR4-mediated IL-10, IL-1β, and TNF-α, respectively; 0.018 and 0.015 for TLR1-2 -mediated IL-10 and IL-1β). Hierarchical clustering generated 3 distinct clusters of patients and a fourth group of “unclustered” individuals. No relationship was observed between the observed immune clusters and the clinical disease phenotype.Conclusions: Although a clinically useful outcome was not observed through hierarchical clustering, our study provides a rationale for using an UML approach to stratify patients. The study also highlights the predominance of hypo-inflammatory innate immune responses as a key mechanism in the pathogenesis of IBD.

Many paediatric healthcare professionals are increasingly concerned about the long-term secondary impact of the COVID-19 pandemic on the care of children and young people (CYP) with chronic conditions. Those of us working in paediatric gastroenterology now lack the ability to provide the same level of diagnostic care and ongoing management to our patients, particularly the large number with inflammatory bowel disease (IBD). With all elective endoscopy cancelled, difficulty in obtaining day-case infusions and telemedicine becoming the norm, many professionals are justifiably uncomfortable. There is little known about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on those CYP with IBD, or on patients with systemic immunosuppression, although the small amount of data derived thus far indicates mild disease in …

Aim: We assessed growth in a paediatric inflammatory bowel disease (PIBD) cohort. Methods: Paediatric inflammatory bowel disease patients were eligible if they were diagnosed at Southampton Children's Hospital from 2011 to 2018. Weight and height standard deviation scores (SDS) were retrieved. Mean SDS values, SDS change and anti-TNF status were analysed at diagnosis and during follow-up. Results: Four hundred and ninety patients were included, 313 with Crohn's disease (CD). CD patients presented with mean height SDS −0.13, −0.1 at 1-year, −0.11 at 2-years and −0.03 at 5 years, reflecting preserved linear growth. There was no significant height-SDS change from diagnosis to 5-year follow-up, +0.12, 95%-CI: 0.48 to −0.24. Mean weight-SDS at diagnosis was −0.39, driven by CD patients (−0.65). Mean weight-SDS approached 0 after 1 year and remained at the 50th centile throughout follow-up. Growth in ulcerative colitis was maintained. In multivariable regression males had worse height growth from diagnosis to transition (P =.036). Anti-TNF treatment (P =.013) and surgical resection (P =.005) were also associated with poorer linear growth. Patients treated with anti-TNF therapy had lower height-SDS compared to those never treated with anti-TNF at 1 year (−0.2 vs −0.01, P =.22), 2-years (−0.27 vs −0.01, P =.07) and 5 years (−0.21 vs 0.25, P =.051). Conclusion: Height was generally maintained in Crohn's disease, and impaired linear growth was rare in this cohort.

Aim: Maintenance enteral nutrition (MEN) is routinely used in Paediatric Crohn's Disease (CD) to prolong remission although there is limited evidence for efficacy and a lack of formal guidelines. This study surveyed patients’, parents’ and professional experience with MEN. Methods: Two questionnaires were developed to survey the experience of MEN; (i) Patients/Parents (children >10 years of age aimed to complete independently) and (ii) Dietitians. Questionnaires were sent to families prescribed MEN after exclusive enteral nutrition (EEN) between 2015‐17 (n = 77) and dietitians working in paediatric regional centres in UK (n = 23). Results: Response rate to the questionnaires was 53% patients, 62% parents and 83% dietitians. Patients/parents reported medical/dietetic advice to be the primary factor affecting compliance, 30% patients reported side effects. Fifty‐six per cent of patients/58% parents stated a preference for dietary advice rather than MEN. Dietetic responses indicated 79% used MEN after EEN as standard procedure and 79% did not have exit criteria for MEN. Sixty‐eight per cent perceived the taste was the primary factor affecting patient compliance. Conclusion: Patients’ perception of the usefulness of MEN differs to professionals. This study highlights the extensive practice of MEN after EEN in clinical remission, which may not be nutritionally indicated. Patient preference is for dietary advice rather than MEN.

Objective In newly diagnosed paediatric patients with moderate-to-severe Crohn’s disease (CD), infliximab (IFX) is initiated once exclusive enteral nutrition (EEN), corticosteroid and immunomodulator therapies have failed. We aimed to investigate whether starting first-line IFX (FL-IFX) is more effective to achieve and maintain remission than conventional treatment. Design In this multicentre open-label randomised controlled trial, untreated patients with a new diagnosis of CD (3–17 years old, weighted Paediatric CD Activity Index score (wPCDAI) >40) were assigned to groups that received five infusions of 5 mg/kg IFX at weeks 0, 2, 6, 14 and 22 (FL-IFX), or EEN or oral prednisolone (1 mg/kg, maximum 40 mg) (conventional). The primary outcome was clinical remission on azathioprine, defined as a wPCDAI

AIM Paediatric Crohn's disease (CD) is associated with growth delay and poor nutritional status. Maintenance enteral nutrition (MEN) supplementation is a potential adjunct to improve growth/prolong remission. METHODS Newly diagnosed CD patients were identified. Anthropometry, treatments and outcomes were collected for 12 months following diagnosis. Data are presented as medians. RESULTS A total of 102 patients were identified (age = 13 years, 76% male), 58 (57%) completed exclusive enteral nutrition (EEN) as induction therapy, and 77 (75%) entered clinical remission. Following induction, 58 (57%) of all patients continued MEN and 44 (43%) consumed normal diet (ND). BMI Z-score increased (diagnosis-12 months) for EEN (-1.41 to -0.21 (p =

The incidence of early-onset paediatric inflammatory bowel disease is increasing worldwide. Defined as a diagnosis of Crohn's disease, ulcerative colitis, or inflammatory bowel disease unclassified before the age of 10 years, the disease is complex, multifactorial, and lifelong, and affects nutrition and psychological wellbeing. Over 200 genes have been implicated and a further 52 genes are known to cause monogenic disease, often presenting in infancy. Heritability of early-onset inflammatory bowel disease is hypothesised to be between that of infantile-onset (ie

OBJECTIVES: Monogenic inflammatory bowel disease (IBD) comprises rare Mendelian causes of gut inflammation, often presenting in infants with severe and atypical disease. This study aimed to identify clinically relevant variants within 68 monogenic IBD genes in an unselected pediatric IBD cohort. METHODS: Whole exome sequencing was performed on patients with pediatric-onset disease. Variants fulfilling the American College of Medical Genetics criteria as "pathogenic" or "likely pathogenic" were assessed against phenotype at diagnosis and follow-up. Individual patient variants were assessed and processed to generate a per-gene, per-individual, deleteriousness score. RESULTS: Four hundred one patients were included, and the median age of disease-onset was 11.92 years. In total, 11.5% of patients harbored a monogenic variant. TRIM22-related disease was implicated in 5 patients. A pathogenic mutation in the Wiskott-Aldrich syndrome (WAS) gene was confirmed in 2 male children with severe pancolonic inflammation and primary sclerosing cholangitis. In total, 7.3% of patients with Crohn's disease had apparent autosomal recessive, monogenic NOD2-related disease. Compared with non-NOD2 Crohn's disease, these patients had a marked stricturing phenotype (odds ratio 11.52, significant after correction for disease location) and had undergone significantly more intestinal resections (odds ratio 10.75). Variants in ADA, FERMT1, and LRBA did not meet the criteria for monogenic disease in any patients; however, case-control analysis of mutation burden significantly implicated these genes in disease etiology. DISCUSSION: Routine whole exome sequencing in pediatric patients with IBD results in a precise molecular diagnosis for a subset of patients with IBD, providing the opportunity to personalize therapy. NOD2 status informs risk of stricturing disease requiring surgery, allowing clinicians to direct prognosis and intervention.

ObjectiveTo use repeated measurements of weight, length and head circumference to generate growth centile charts reflecting real-world growth of a population of very preterm infants with a well-described nutritional intake close to current recommendations.DesignInfants born before 30 weeks gestational age (GA) were recruited. Infants received nutrition according to an integrated care pathway, with nutrient intake recorded daily, weight recorded twice-weekly and length and head circumference weekly. The LMS method was used to construct growth centile charts between 24 and 36 weeks corrected GA for each parameter.SettingA single tertiary neonatal unit in England.Patients212 infants (124 male) (median GA at birth: 27.3 weeks, median birth weight: 900 g).ResultsMedian daily energy, protein, carbohydrate and fat intake were within 3% of published recommendations. The total number of measurements recorded was 5944 (3431 for weight, 1227 for length and 1286 for head circumference). Centile charts were formed for each parameter. Data for male and female infants demonstrated similar patterns of growth and were pooled for LMS analysis. A web application was created and published (bit.ly/sotongrowth) to allow infants to be plotted on these charts with changes in SD score of measurements reported and graphically illustrated.ConclusionsThese charts reflect growth in a real-world cohort of preterm infants whose nutrient intakes are close to current recommendations. This work demonstrates the feasibility of forming growth charts from serial measurements of growing preterm infants fed according to current recommendations which will aid clinicians in setting a benchmark for achievable early growth.

We are grateful for Menon et al ’s editorial in response1 to our recent article.2 They set out several pertinent points and issue a call to action for future research. Menon et al question whether ‘catch-up’ growth of infants with intrauterine growth restriction (IUGR) contributed substantially to the overall change in weight SD Score (∆SDS) between birth and 36 weeks corrected gestational age (CGA). Further analysis of our data sheds some light on this proposition. Infants with IUGR (defined as a birth weight of at least 1.33 SD below the 1990 British Growth Reference mean) grew slightly more than their non-IUGR counterparts (table 1). View this table: Table 1 Mean change in weight SD Score between birth and 36 weeks CGA in infants without IUGR, …

Background The human leucocyte antigen (HLA) complex, located at chromosome 6p21.3 is a highly polymorphic region containing the classical class I and II HLA genes. The region is highly associated with inflammatory bowel disease (IBD), largely through genome-wide association studies (GWAS). Aims To review the role of HLA in immune function, summarise data on risk/protective HLA genotypes for IBD, discuss the role of HLA in IBD pathogenesis, treatment and examine limitations that might be addressed by future research. Methods An organised search strategy was used to collate articles describing HLA genes in IBD, including Crohn's disease and ulcerative colitis. Results All classical HLA genes with variation (including HLA-A, B, C, DRB1, DQA1, DQB1, DPA1 and DPB1) harbour IBD-associated genotypes. The most implicated gene is HLA-DRB1, with HLA-DRB1*03:01 the most associated risk allele in both Crohn's disease and ulcerative colitis. Elucidating precise disease associations is challenging due to high linkage disequilibrium between HLA genotypes. The mechanisms by which risk alleles cause disease are multifactorial, with the best evidence indicating structural and electrostatic alteration impacting antigen binding and downstream signalling. Adverse medication events have been associated with HLA genotypes including with thiopurines (pancreatitis) and anti-TNF agents (antibody formation). Conclusions The HLA complex is associated with multiple risk/protective alleles for IBD. Future research utilising long-read technology, ascertainment of zygosity and integration in disease modelling will improve the functional understanding and clinical translation of genetic findings.

Background Next-generation sequencing is revolutionising diagnosis and treatment of rare diseases, however its application to understanding common disease aetiology is limited. Rare disease applications binarily attribute genetic change(s) at a single locus to a specific phenotype. In common diseases, where multiple genetic variants within and across genes contribute to disease, binary modelling cannot capture the burden of pathogenicity harboured by an individual across a given gene/pathway. We present GenePy, a novel gene-level scoring system for integration and analysis of next-generation sequencing data on a per-individual basis that transforms NGS data interpretation from variant-level to gene-level. This simple and flexible scoring system is intuitive and amenable to integration for machine learning, network and topological approaches, facilitating the investigation of complex phenotypes. Results Whole-exome sequencing data from 508 individuals were used to generate GenePy scores. For each variant a score is calculated incorporating: i) population allele frequency estimates; ii) individual zygosity, determined through standard variant calling pipelines and; iii) any user defined deleteriousness metric to inform on functional impact. GenePy then combines scores generated for all variants observed into a single gene score for each individual. We generated a matrix of ~ 14,000 GenePy scores for all individuals for each of sixteen popular deleteriousness metrics. All per-gene scores are corrected for gene length. The majority of genes generate GenePy scores

BackgroundPreviously published data have demonstrated that preterm infants experience a fall across marked centile lines for weight in early life with early poor head growth also reported. This study describes a single neonatal unit’s experience of longitudinal change in weight, head circumference (HC) and length in a cohort of preterm infants born MethodsData were collected from a single neonatal unit between July 2012 and June 2017. This period followed the introduction of improved nutritional guidelines. Patients were grouped according to their gestational age at birth. Growth lines were constructed for weight, HC and length in each gestational age group from the median measures and compared with reference centile lines.ResultsData were analysed from 396 patients consisting of 2808, 1991 and 2004 measures for weight, HC and length, respectively. Longitudinal growth plots did not show an initial absolute weight loss in any of the subgroups. Across all groups, the mean change in SD score between birth and 36 weeks was −0.27 (95% CI −0.39 to −0.15).ConclusionsThis description of longitudinal growth in a cohort of preterm infants demonstrates that early postnatal growth failure is not inevitable, with most infants growing along a trajectory close to their birth centile. There is no evidence of a 2 marked centile line weight decrease or weight loss. These data provide evidence to suggest that extrauterine weight gain tracking centile lines can be achieved.

An “author pays” publishing model is the only fair way to make biomedical research findings accessible to all, say Matthew Kurien and David S Sanders, but James J Ashton and R Mark Beattie worry that it can lead to bias in the evidence base towards commercially driven results

Up to 25% of inflammatory bowel disease (IBD) presents during childhood, often with severe and extensive disease, leading to significant morbidity including delayed growth and nutritional impairment. The classical approach to management has centred on differentiation into Crohn’s disease (CD) or ulcerative colitis (UC), with subsequent treatment based on symptoms, results and complications. However, IBD is a heterogeneous condition with substantial variation in phenotype, disease course and outcome, so whilst effective treatment exists one size does not fit all. The ability to predict disease course at diagnosis, alongside tailoring medications based on response gives the potential for a more ‘personalised approach’. The move to a pre-emptive strategy to prevent IBD-related complications, whilst simultaneously minimising side effects and long-term toxicity from therapy, particularly in those with relatively indolent disease, has the potential to revolutionise care. In very early-onset IBD, personalised approaches to diagnosis and management have become the standard of treatment enabling clinicians to significantly alter the outcomes of the few children with monogenic disease. However, the promise of discoveries in genomics, microbiome and transcriptomics in paediatric IBD has not yet translated to clinical application for the vast majority of patients. Despite this, the opportunity presents itself to apply data gathered at diagnosis and follow-up to predict which patients are likely to progress to complicated disease, which will respond well and which will require additional therapy. Using complex mathematics and innovative, cutting-edge machine learning (ML) techniques gives the potential to use this data to develop personalised clinical care algorithms to treat patients more effectively, reduce toxicity and improve outcome. In this review, we will consider current management of paediatric IBD, discuss how precision medicine is making inroads into clinical practice already, examine the contemporary studies applying data to stratify patients and explore how future management may be revolutionised by personalisation with clinical, genomic and other multi-omic data.

Introduction: Long-term, sustained, remission is the ultimate goal of contemporary inflammatory bowel disease (IBD) therapy. Avoiding complications, surgery and malignancy, alongside minimizing the side effects of medications are vital. However, the reality of treatment involves patients losing response to therapy, or developing complications requiring cessation of medication. The reasons underlying this are numerous and include medication and host-related influences. Underpinning the response to medication, long-term outcomes and loss of response are individual etiological factors including the molecular cause of disease and individual pharmacogenomic influences.Areas covered: In this review, we discuss the long-term outcome of IBD, with a focus on pediatric-onset illness and discuss the factors leading to loss of treatment response whilst briefly considering the future of personalized therapy as a strategy to improve long-term outcomes.Expert opinion: Research findings are now moving toward clinical translation, including application of novel medications targeting new pathways. The integration of biological and multiomic data to predict disease outcome will provide personalized therapeutic management.

BACKGROUND: The lack of evidence-based outcomes data leads to uncertainty in developing treatment regimens in children newly diagnosed with Ulcerative Colitis (UC). We hypothesized that pre-treatment clinical, transcriptomic, and microbial factors predict disease course. METHODS: We performed an inception cohort study of 428 paediatric UC patients receiving standardised mesalazine or corticosteroids (CS), with pre-established criteria for escalation to thiopurines or anti-TNFα. RNA sequencing (n=206) defined pre-treatment rectal gene expression. 16S sequencing (n=343) characterized rectal/fecal microbiota. The primary outcome was Week 52 CS-free remission (SFR) with no therapy beyond mesalazine. FINDINGS: Week 52 SFR was achieved in 150/400 (38%) participants; 74/400 (19%) received thiopurines alone, 12¾00 (31%) received anti-TNFα, and 25/400 (6%) colectomy. Lower baseline clinical severity, higher baseline hemoglobin, and Week 4 clinical remission were associated with achieving Week 52 SFR (logistic model AUC:0.70 (95% CI 0.65–0.75), specificity 77% (CI 71–82), n=386). Baseline severity and week 4 remission were validated inan independent cohort of 274 participants. An antimicrobial peptide gene signature (OR:0.6, p=0.002) and Ruminococcaceae (OR:1.4, p=0.04) and Sutterella (OR: 0.8, p=0.05) abundance were independently associated with SFR after adjusting for the clinical predictors. Amongst moderate-to-severe patients, escalation to anti-TNFα was associated with increased baseline clinical severity and decreased hemoglobin, serum 25 (OH) D, and rectal eosinophils (logistic model AUC:0.78 (95% CI 0.72–0.84), specificity 85% (CI 78–93), n=232). A rectal transportgene signature (OR:0.3, p=0.0006) and Oscillospira abundance (OR:0.6, p=0.02) were independently associated with escalation to anti-TNFα after adjusting for the clinical predictors. INTERPRETATION: Our findings support the utility of using initial clinical activity and treatment response by 4 weeks to predict Week 52 CS-free remission with mesalazine alone in children newly diagnosed with UC. The development of personalized clinical and biological signatures holds the promise of informing UC therapeutic decisions. FUNDING: National Institutes of Health

Background: Pediatric inflammatory bowel disease (PIBD) is associated with a diagnostic delay. Blood tests are a routine part of the work-up in children with chronic abdominal symptoms (pain, diarrhea). Normal blood tests cannot exclude PIBD. We analyzed blood results at diagnosis over a 5-year period. Methods: Patients diagnosed from 2013 to 2017 were identified from the Southampton-PIBD database. Results were obtained up to 100 days before diagnostic endoscopy. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), albumin, hemoglobin, platelets, packed cell volume (PCV), white cell count (WCC), and alanine transferase (ALT) were analyzed. Hierarchical clustering was applied to normalized results. Results: Two hundred fifty-six patients were included (Crohn's disease [CD], 151; ulcerative colitis [UC], 95; IBD-unclassified, 10; median age, 13.48 years; 36.7% female). Hierarchical clustering of patients revealed novel groupings enriched for CD and UC, characterized by specific patterns of results. In PIBD, 9% presented with all normal blood tests, 21.9% with normal CRP and ESR. Abnormal results were seen in all tests (ESR, 56.4% of patients; CRP, 53.4%; albumin, 28%; hemoglobin, 61.9%; platelets, 55.6%; PCV, 64.6%; WCC, 22.7%; and ALT, 7.2%). Normal inflammatory markers were more common in UC compared with CD (UC, 34%; CD, 15.8%; P = 0.0035). UC (14.4% normal) presented with all normal results more frequently than CD (CD, 5.3%; P = 0.02). CRP, ESR, and platelets were significantly higher in CD compared with UC. Albumin and hemoglobin were significantly lower. Conclusions: Most cases of PIBD present with >1 abnormal blood result, although 1/11 patients presents with normal blood tests and 1/5 present with normal inflammatory markers. Hierarchical clustering offers the potential to produce novel groupings to inform disease categorization and best management.

Paediatric inflammatory bowel disease (PIBD), consisting of Crohn's disease, ulcerative colitis and inflammatory bowel disease unclassified, is a chronic inflammatory condition associated with significant morbidity. The incidence of PIBD is increasing and disease phenotype remains more severe than adult onset disease. Diagnosis of PIBD is often slow and requires referral to specialist services; however, the emergence of faecal calprotectin as a tool for prioritizing further investigation, alongside improved use of treatments (including anti-TNF monoclonal antibody therapy) is changing diagnosis and management. Whilst significant challenges remain in the longer-term treatment of PIBD, including growth, nutrition and management of refractory disease there remains a strong research focus on understanding underlying disease pathogenesis and a move towards personalized medicine. This review describes investigations, diagnosis and management of PIBD and presents the most up to date evidence on nutritional and medical management.